FIP-2, a coiled-coil protein, links Huntingtin to Rab8 and modulates cellular morphogenesis

Huntington's disease is characterised by the death of cortical and striatal neurons, and is the result of an expanded polyglutamine tract in the Huntingtin protein [1]. Huntingtin is present on both endocytic and secretory membrane organelles but its function is unclear [2,3]. nab GTPases regulate both of these transport pathways [4], We have previously shown that nabs controls polarised membrane transport by modulating cell morphogenesis [5]. To understand nabs-mediated processes, we searched for Rab8-interacting proteins by the yeast two-hybrid system. Here, we report that Huntingtin is linked to the nabs protein through FIP-2, a tumour necrosis factor-alpha (TNF-alpha)-inducible coiled coil protein related to the NEMO protein [6,7]. The activated form of nabs interacted with the amino-terminal region of FIP-2, whereas dominant-negative nabs did not. Huntingtin bound to the carboxy-terminal region of FIP-2. Coexpressed FIP-2 and Huntingtin enhanced the recruitment of Huntingtin to Rab8 positive vesicular structures, and FIP 2 promoted cell polarisation in a similar way to nabs. We propose a model in which Huntingtin, together with FIP-2 and nabs, are part of a protein network that regulates membrane trafficking and cellular morphogenesis.